EP2340025A1 - Antagonistes des récepteurs cgrp - Google Patents

Antagonistes des récepteurs cgrp

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Publication number
EP2340025A1
EP2340025A1 EP09818345A EP09818345A EP2340025A1 EP 2340025 A1 EP2340025 A1 EP 2340025A1 EP 09818345 A EP09818345 A EP 09818345A EP 09818345 A EP09818345 A EP 09818345A EP 2340025 A1 EP2340025 A1 EP 2340025A1
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EP
European Patent Office
Prior art keywords
halo
substituted
unsubstituted
independently selected
phenyl
Prior art date
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EP09818345A
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German (de)
English (en)
Other versions
EP2340025B1 (fr
EP2340025A4 (fr
Inventor
Donnette D. Staas
Ian M. Bell
Harold G. Selnick
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Merck Sharp and Dohme LLC
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Merck Sharp and Dohme LLC
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • CGRP Calcitonin Gene-Related Peptide
  • CGRP is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA and is widely distributed in the central and peripheral nervous system.
  • CGRP is localized predominantly in sensory afferent and central neurons and mediates several biological actions, including vasodilation.
  • CGRP is expressed in alpha- and beta-forms that vary by one and three amino acids in the rat and human, respectively.
  • CGRP-alpha and CGRP-beta display similar biological properties. When released from the cell, CGRP initiates its biological responses by binding to specific cell surface receptors that are predominantly coupled to the activation of adenylyl cyclase.
  • CGRP receptors have been identified and pharmacologically evaluated in several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth muscle origin. Based on pharmacological properties, these receptors are divided into at least two subtypes, denoted CGRPi and CGRP 2 .
  • Human ⁇ -CGRP-(8-37) a fragment of CGRP that lacks seven N-terminal amino acid residues, is a selective antagonist of CGRPi, whereas the linear analogue of CGRP, diacetoamido methyl cysteine CGRP ([Cys(ACM)2,7]CGRP), is a selective agonist of CGRP 2 .
  • CGRP is a potent neuromodulator that has been implicated in the pathology of cerebrovascular disorders such as migraine and cluster headache.
  • elevated levels of CGRP in the jugular vein were found to occur during migraine attacks (Goadsby et al., Ann. Neurol., 1990, 28, 183-187), salivary levels of CGRP are elevated in migraine subjects between attacks (Bellamy et al., Headache, 2006, 46, 24-33), and CGRP itself has been shown to trigger migrainous headache (Lassen et al., Cephalalgia, 2002, 22, 54-61).
  • the CGRP antagonist B ⁇ BN4096BS has been shown to be effective in treating acute attacks of migraine (Olesen et al., New Engl. J. Med., 2004, 350, 1104-1110) and was able to prevent headache induced by CGRP infusion in a control group (Petersen et al., Clin. Pharmacol. Ther,, 2005, 77, 202-213).
  • CGRP-mediated activation of the trigemino vascular system may play a key role in migraine pathogenesis. Additionally, CGRP activates receptors on the smooth muscle of intracranial vessels, leading to increased vasodilation, which is thought to contribute to headache pain during migraine attacks (Lance, Headache Pathogenesis: Monoamines, Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997, 3-9).
  • the middle meningeal artery the principle artery in the dura mater, is innervated by sensory fibers from the trigeminal ganglion which contain several neuropeptides, including CGRP.
  • Trigeminal ganglion stimulation in the cat resulted in increased levels of CGRP, and in humans, activation of the trigeminal system caused facial flushing and increased levels of CGRP in the external jugular vein (Goadsby et al., Ann. Neurol., 1988, 23, 193-196).
  • Electrical stimulation of the dura mater in rats increased the diameter of the middle meningeal artery, an effect that was blocked by prior administration of CGRP(8-37), a peptide CGRP antagonist (Williamson et al., Cephalalgia, 1997, 17, 525-531).
  • Trigeminal ganglion stimulation increased facial blood flow in the rat, which was inhibited by CGRP(8-37) (Escott et al., Brain Res. 1995, 669, 93-99), Electrical stimulation of the trigeminal ganglion in marmoset produced an increase in facial blood flow that could be blocked by the non-peptide CGRP antagonist BIBN4096BS (Doods et al., Br. J. Pharmacol, 2000, 129, 420-423). Thus the vascular effects of CGRP may be attenuated, prevented or reversed by a CGRP antagonist.
  • CGRP-mediated vasodilation of rat middle meningeal artery was shown to sensitize neurons of the trigeminal nucleus caudalis (Williamson et al., The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, and Adrenomedullin, Austin Bioscience, 2000, 245-247).
  • CGRP Calcitonin Gene-Related Peptide
  • Amylin Amylin
  • Adrenomedullin CGRP-Related Peptide
  • distention of dural blood vessels during migraine headache may sensitize trigeminal neurons.
  • Some of the associated symptoms of migraine, including extracranial pain and facial allodynia may be the result of sensitized trigeminal neurons (Burstein et al., Ann. Neurol, 2000, 47, 614-624).
  • a CGRP antagonist may be beneficial in attenuating, preventing or reversing the effects of neuronal sens
  • CGRP antagonists The ability of the compounds of the present invention to act as CGRP antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans.
  • disorders include migraine and cluster headache (Doods, Curr Opin Inves Drugs, 2001, 2 (9), 1261-1268; Edvinsson et ah, Cephalalgia, 1994, 14, 320-327); chronic tension type headache (Ashina et al., Neurology, 2000, 14, 1335-1340); pain (Yu et al., Eur. J.
  • the present invention relates to compounds that are useful as ligands for CGRP receptors, in particular antagonists for CGRP receptors, processes for their preparation, their use in therapy, pharmaceutical compositions comprising them and methods of therapy using them.
  • the present invention is directed to compounds of formula I:
  • the present invention is directed to compounds of the formula I:
  • a ⁇ is selected from:
  • each alkyl is independently unsubstituted or substituted with 1-5 halo-
  • a 2 is selected from:
  • a 3 is selected from:
  • a 4 is selected from:
  • a 5 and A 7 are each independently selected from: (1) -O-,
  • a 6 and A 8 are independently selected from:
  • each alkyl is independently unsubstituted or substituted with 1-5 halo-
  • E a , E and E c are each independently selected from:
  • E c is selected from:
  • L is selected from:
  • Q is selected from:
  • R 4 is selected from:
  • R 5 is selected from:
  • R 6 and R 7 are each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, Ihiazolyl, indolyl, indazolyl, benzimidazolyl, and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • R 6 and R 7 and the carbon atom to which they are attached join to form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, dioxolanyl, dioxanyl, indanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, mo ⁇ holinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiapyranyl, oxetanyl, thietanyl and tetrahydrothienyl, wherein the sulfur is optionally oxidized to the s
  • phenyl or heterocycle wherein heterocycle is selected from: pyridyl, pyrirnidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, imidazolyl, furanyl, tetrahydrofuranyl, Ihiazolyl and oxazolyl, wherein the phenyl or heterocycle is optionally fused to the ring, and which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: (i) halo,
  • R 8 is independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • R 7 and R 8 and the atoms to which they are attached join to form a A-, 5-, 6- or 1- membered alkyl- or heteroalkyl-ring optionally containing an additional heteroatom selected from N, O 5 and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is unsubstituted or substituted with 1-4 substituents each independently selected from: (a) halo,
  • R l ⁇ is independently selected from:
  • R 11 is independently selected from the group consisting of: phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthry ⁇ , azepinyl, azepanyl, azetidinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyi, benzopyranyl, benzothiopyranyl, benzofury ⁇ , 1,3-benzodioxolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, chromanyl, cinnolinyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzolhiopyranyl sulfone, furyl, furanyl,
  • R 12 , R n , R 14 , R i 5a and R t5b are each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1 -5 substituents each independently selected from: (i) halo, (ii) which is unsubstituted or substituted with 1-5 halo, and
  • phenyl or heterocycle wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thietanyl and tetrahydrothienyl, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is imsubstituted or substituted with 1-5 substituents each independently selected from;
  • phenyl or heterocycle wherein said heterocycle is selected from: pyrldyl. pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morphoHnyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1 -5 substituents each independently selected from: (i) halo,
  • R p0 is independently selected from:
  • J is independently selected from: (1)
  • Y is independently selected from:
  • W is independently selected from: (1) a bond
  • Z is independently selected from:
  • R 18 are each independently selected from:
  • phenyl or heterocycte wherein said heterocycle is selected from pyridyf, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: (i) -OR a ,
  • g y which is unsubstituted or substituted with 1-6 halo, (5) phenyl or heterocycle wherein heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from: imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, isoxazolyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: (i) halo,
  • phenyl or heterocycle wherein heterocycle is selected from; imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydrofuryl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, thiazolyl, thienyl, triazolyl, isoxazolyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
  • phenyl or heterocycle wherein heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azetidinyl, piperaziny ⁇ , pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • R a is independently selected from:
  • Ci-galkyl which is unsubstituted or substituted with 1-7 substituents each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azet ⁇ dinyl, furanyl, piperazinyl, pyrrolidinyl, morphohnyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1 -3 substituents each independently selected from: (i) halo,
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: (a) halo, (b) -CN,
  • R b and R° are independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azelidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
  • R d is independently selected from:
  • Ci-ealkyl which is unsubstituted or substituted with 1-4 substituents each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyi, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1 -3 substituents each independently selected from: (i) halo, (ii) -OR a , (iii) -Ci-galkyl, which is unsubstituted or substituted with 1-6 halo, and
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyi, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
  • R e and R f are independently selected from:
  • R s and R are independently selected from:
  • A* is selected from:
  • a 1 is -NR 8 , wherein R 8 is preferably H or -C ⁇ alkyl (preferably methyl).
  • a 2 is selected from:
  • R 6 and R 7 are each hydrogen, or one of R 6 and R 7 is hydrogen, and the other is linked together with an R 6 or R 7 from the A 3 group to form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, dioxolanyl, dioxanyl, indanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, letrahydropyranyl,
  • R 6 and R 7 are each hydrogen, or one of R 6 and R 7 is hydrogen, and the other is is linked together with an R 6 or R 7 from the A 2 group to form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, dioxolanyl, dioxanyl, indanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyr
  • a 4 is selected from:
  • a 4 is a bond
  • a 5 and A 7 are each independently selected from:
  • a 5 and A 7 are each a bond.
  • a 6 and A 8 are independently selected from:
  • R 15a is halogen or which is optionally substituted with halogen.
  • E a , E b and E c are each independently selected from:
  • E b is nitrogen
  • E a and E c are each CH
  • L is selected from:
  • R 4 is selected from:
  • R PG is selected from: (1) hydrogen, or
  • J is selected from:
  • Y is selected from:
  • W is selected from:
  • Z is selected from:
  • R e and R f are independently selected from:
  • cycloalkyl typically, cyclopropyl
  • R 6 and R 7 are each hydrogen or -C t ⁇ alkyl (typically, methyl).
  • the present invention is further directed to the exemplary compounds 1 and 2 of formula
  • the invention is also directed to medicaments or pharmaceutical compositions for treating diseases or disorders in which CGRP is involved, such as migraine, which comprise a compound of any of formulas (I) to (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention is also directed to the use of a compound of any of formulas (I) to (III) for treating diseases or disorders in which CGRP is involved, such as migraine.
  • the invention is further directed to a method for the manufacture of a medicament or a composition for treating diseases or disorders in which CGRP is involved, such as migraine, comprising combining a compound of any of formulas (I) to (III) with one or more pharmaceutically acceptable carriers.
  • each such variable may be the same or different from each similarly designated variable.
  • R a is recited multiple times in formula I
  • each Ra in formula I may independently be any of the substructures defined under R a .
  • the invention is not limited to structures and substructures wherein each Ra must be the same for a given structure. The same is true with respect to any variable appearing multiple times in a structure or substructure.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers, Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
  • the present invention includes compounds of formula I wherein on or more hydrogen atoms are replaced by deuterium.
  • Tautomers of compounds defined in any of formulas (I) to (III) are also included within the scope of the present invention.
  • keto and enol forms are included within the scope of the present invention.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixt ure, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • substituents which may form a ring structure (for instance R may form a ring with R ), not all combinations of substituents are susceptibe to ring formation. Moreover, even those substituents capable of ring formation may or may not form a ring structure.
  • halo or halogen as used herein are intended to include chloro, fluoro, bromo and iodo,
  • Ci-galkyl is intended to mean linear and branched structures having no carbon-to-carbon double or triple bonds.
  • Ci-galkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that Ci-galkyl specifically includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and hexyl.
  • Co or Coalkyl is defined to identify the presence of a direct covalent bond, "Cycloalkyl" is an alkyl, part or all of which which forms a ring of three or more atoms.
  • alkenyl means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon double bond, wherein hydrogen may be replaced by an additional carbon-to-carbon double bond.
  • C2 ⁇ 6 a lkenyl for example, includes ethenyl, propenyl, 1 -methylethenyl, butenyl and the like.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic, Examples of such aryl elements include phenyl, napthyl, tetrahydronaplhyl, indanyl, or biphenyl.
  • heterocycle or “heterocyclic”, as used herein except where noted, represents a stable 5- to 7-membered monocyclic- or stable 8- to 1 1-membered bicyclic heterocyclic ring system which is either saturated or unsaturated, and which consists of carbon atoms and from one to six heteroatoms selected from the group consisting of N, O, S, P and Si, and wherein the nitrogen, sulfur and phosphorus heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic groups include, but are not limited to, azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazolidinone, imidazoline, imidazolinone, indoline, isochroman, isoindoline, isothiazoline, isolhiazoiidine, isoxazoline, isoxazolidine, morpholine, mo ⁇ holinone, oxazoline, oxazolidine, oxazolidinone, oxetane, 2-oxohexahydroazepin, 2-oxopiperazine, 2-oxopiperidine, 2- oxopyrrolidine, piperazine, piperidine, pyran, pyrazolidine, pyr
  • heteroaryl represents a stable 5- to 7-membered monocyclic- or stable 9- to 10-membcred fused bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to six heteroatoms selected from the group consisting of N, O, S, P and Si, and wherein the nitrogen, sulfur and phosphorus heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole,
  • alkoxy as in Ci-Cg alkoxy, is intended to refer to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched and cyclic configuration. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like,
  • phrases "pharmaceutically acceptable” is used herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the sails prepared from organic acids such as acetic, propionic, succinic, giycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like,
  • the number of certain variables present in certain instances is defined in terms of the number of carbons present.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesu ⁇ fonic, benzoic, carnphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p ⁇ toluenesulfonic acid, and the like.
  • the salts are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
  • the subject compounds are useful in a method of antagonism of CGRP receptors in a patient such as a mammal in need of such antagonism comprising the administration of an effective amount of the compound.
  • the present invention is directed to the use of the compounds disclosed herein as antagonists of CGRP receptors. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention.
  • Another embodiment of the present invention is directed to a method for the treatment, control, amelioration, or reduction of risk of a disease or disorder in which the CGRP receptor is involved in a patient that comprises administering to the patient a therapeutically effective amount of a compound that is an antagonist of CGRP receptors.
  • the present invention is further directed to a method for the manufacture of a medicament for antagonism of CGRP receptors activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
  • the subject treated in the present methods is generally a mammal, for example a human being, male or female, in whom antagonism of CGRP receptor activity is desired.
  • therapeutically effective amount means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • treatment refers both to the treatment and to the prevention or prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Such term in relation to pharmaceutical composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
  • the terms "administration of 1 or "administering a” compound shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
  • the ability of the compounds of the present invention to act as CGRP antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans.
  • the compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of one or more of the following conditions or diseases; headache; migraine; cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; diabetes; non-insulin dependent diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial hyperreactivity, asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; psoriasis; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, skin rosaceousness and erythema; inflammatory bowel disease, irritable bowel syndrome, cystitis; and other conditions that may be treated or prevented by
  • the subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
  • the subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of any of Formulas (I) to (III) or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compounds of any of Formulas (I) to (III).
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of any of Formulas (I) to (III) is preferred.
  • the combination therapy may also include therapies in which the compound of any of Formulas (I) to (HI) and one or more other drugs are administered on different overlapping schedules.
  • the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of any of Formulas (I) to (III).
  • the present compounds may be used in conjunction with an an antimigraine agent, such as ergotamine and dihydroergotamine, or other serotonin agonists, especially a 5-HT I B/I D agonist, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, and rizatriptan, a 5-HT] D agonist such as PNU- 142633 and a 5-HTi F agonist such as LY334370; a cyclooxygenase inhibitor, such as a selective cyclooxygenase ⁇ 2 inhibitor, for example rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidal anti-inflammatory agent or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as ibuprofen, ketoprofen,
  • the instant compounds may be administered with an analgesic such as aspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine or morphine.
  • an analgesic such as aspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine or morphine.
  • an interleukin inhibitor such as an interleukin-1 inhibitor; an NK-I receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2B antagonist; a bradykinin-1 receptor antagonist; an adenosine Al receptor agonist; a sodium channel blocker, for example lamotrigine; an opiate agonist such as levomethadyl acetate or methadyl acetate; a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptor antagonist, for example indoramin; an alpha receptor agonist; a vanilloid receptor antagonist; a renin inhibitor; a granzyme B inhibitor; a substance P antagonist; an endothelin antagonist; a norepinephrin precursor; anti-anxiety agents such as diazepam, alprazolam, chlordiazepoxide and chlorazepate; serotonin 5HT 2
  • an interleukin inhibitor such as an
  • the present compounds may be used in conjunction with ergot alkaloids other than ergotamine and dihydroergotamine, for example ergonovine, ergonovine, methylergonovine, metergoline, ergoloid mesylates, dihydroergocornine, dihydroergocristine, dihydroergocrypline, dihydro- ⁇ -ergocryptine, dihydro- ⁇ -ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, ⁇ -ergocryptine, ⁇ -ergocryptine, ergosine, ergostane, bromocriptine, or methysergide.
  • ergonovine ergonovine, methylergonovine, metergoline, ergoloid mesylates
  • dihydroergocornine dihydroergocristine, dihydroergocrypline
  • the present compounds may be used in conjunction with a beta- adrenergic antagonist such as timolol, propanolol, atenolol, metoprolol or nadolol, and the like; a MAO inhibitor, for example phenelzine; a calcium channel blocker, for example flunarizine, diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine, lomerizine, verapamil, nifedipine, or prochlorperazine; neuroleptics such as olanzapine, droperidol, prochlorperazine, chlorpromazine and quetiapine; an anticonvulsant such as topiramate, zonisamide, tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine, gabapentin, pregabalin or
  • the present compounds may be used in conjunction with a potentiator such as caffeine, an H2 -antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as oxymetazoline, epinephrine, naphazoHne, xylometazoline, propylhexedrine, or levo- desoxy-ephedrine; an antitussive such as caramiphen, carbetapentane, or dextromethorphan; a diuretic; a prokinetic agent such as metoclopramide or domperidone; a sedating or non-sedating antihistamine such as acrivastine, azatadine, bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, loratadine, phen ⁇ ndamine,
  • the present compounds are used in conjunction with an anti-migraine agent, such as: ergotamine or dihydroergotamine; a 5-HTi agonist, especially a 5-HT J B / I D agonist, in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, avitriptan and rizatriptan, and other serotonin agonists; and a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, in particular, rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib.
  • an anti-migraine agent such as: ergotamine or dihydroergotamine; a 5-HTi agonist, especially a 5-HT J B / I D agonist, in particular, sumatriptan, naratriptan, zolmitript
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the compound of the present invention to the other active ingredient(s) may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1 :1000, or from about 200: 1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used, In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s), and via the same or different routes of administration.
  • the compounds of the present invention may be administered by oral, parenteral
  • intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention are effective for use in humans.
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, solutions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Oral tablets may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Oral tablets may also be formulated for immediate release, such as fast melt tablets or wafers, rapid dissolve tablets or fast dissolve films.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethy I cellulose, methylcellulose, hydroxy-propylmethylceliulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as ⁇ quid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil- in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides,
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • transdermal patches may also be used for topical administration.
  • compositions and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • an appropriate dosage level will generally be about 0,01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • compositions are may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.O 5 and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, or may be administered once or twice per day,
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, given as a single daily dose or in divided doses two to six limes a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, or from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail.
  • the general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.
  • the final product may be further modified, for example, by manipulation of substituents.
  • manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
  • Scheme 1 illustrates a general strategy for the synthesis of the compounds of the present invention via coupling of carboxylic acid A with amine B to give amide C.
  • Standard coupling conditions such as EDC and HOBT with DIEA as base and DMF as solvent, may be successfully employed in this reaction.
  • Other standard coupling conditions may be employed in the synthesis of such amides, including use of an alternative coupling reagent such as BOP, HATU or PyCLU, or activation of the carboxylic acid as an acid anhydride or acid chloride.
  • an alternative coupling reagent such as BOP, HATU or PyCLU
  • various protecting group strategies familiar to one skilled in the art of organic synthesis may be employed to allow preparation of a particular compound of the present invention.
  • amines B used to make the compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures.
  • intermediate 1 (such as commercially available 2H- pyrido[3,2-6][l,4]oxazin-3(4H)-one) may undergo spirocyclization with the known 1,4- dibromobutanone (Meijere et al. (2001) Eur. J. Org. Chem. 20, 3789) to afford spiroketone 2.
  • Condensation of 2 with l-methyl-3,5-dinitropyridinone ( ⁇ hda et al. (1990) Bull. Chem. Soc, Japan 63, 2820) in refluxing methanolic ammonia provides nitropyridine 3 which undergoes iron-mediated reduction to aminopyridine 4.
  • oxazinone 1 may undergo spirocyclization with other dihalides or bis-sulfonates as an alternate approach to the synthesis of intermediates like 3 for use in the preparation of compounds described in the present invention, using methods which are known to those skilled in the art and described in the chemical literature.
  • 2-amino-6-chloro ⁇ yridine 5 is converted to its Boc derivative 6 as described in Williams US2006/028835.
  • ketones 7, such as but not limited to 5-haloindanones, may be subjected to a similar addition-cyclization sequence followed by further derivatization to amines 9, utilizing synthesis procedures described in the chemical literature and known to those skilled in the art.
  • amines 9 utilizing synthesis procedures described in the chemical literature and known to those skilled in the art.
  • Various protecting group strategies and other modifications to the steps in the scheme may be employed, and such modifications would be known to those skilled in the art.
  • manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. Moreover, in some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • a solution of A ⁇ A ⁇ N' ⁇ '-tetramethylethylenediamine (3.3 mL, 22 mmol) in THF (8 mL) is cooled to -20 0 C and treated with n-butyllithium (2.5 M in hexanes, 8.8 mL, 22 mmol) over 10 rain. After stirring for 30 rnin, the mixture is cooled to -78 0 C and treated with a solution of tert-btttyl ( ⁇ -chloropyridin-2-yl)carbamate (2.29 g, 10 mmol) [Williams US2006/028835] in THF (6 mL) over 15 min.
  • the mixture is stirred at rt for 18 h and is then purified directly by HPLC using a reversed phase C 18 column and eluting with a gradient of H 2 ChCH 3 CNiCF 3 CO 2 H - 90:10:0.1 to 5:95:0.1.
  • the pure, product-containing fractions are combined and lyophilized to afford the title compound.
  • NATIVE RECEPTOR BINDING ASSAY The binding of 125 I-CGRP to receptors in SK-N-MC cell membranes according to this procedure may be carried out essentially as described (Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly, according to this procedure, membranes (25 ⁇ g) are incubated in 1 mL of binding buffer [10 mM HEPES > pH 7.4,
  • RECOMBINANT RECEPTOR Human CL receptor (Genbank accession number L76380) is subcloned into the expression vector pIREShyg2 (BD Biosciences Clontech) as a 5'NheI and 3' Pmel fragment.
  • Human RAMPl Genbank accession number AJOOl 014 is subcloned into the expression vector pIRESpuro2 (BD Biosciences Clontech) as a 5'NheI and 3'NotI fragment.
  • HEK 293 cells human embryonic kidney cells; ATCC #CRL-1573
  • DMEM fetal bovine serum
  • FBS fetal bovine serum
  • Peptomycin 100 units/mL penicillin and 100 ⁇ g/mL streptomycin
  • Stable cell line generation is accomplished by co -trans fecting 10 ⁇ g of DNA with 30 ⁇ g Lipofectamine 2000 (Invitrogen) in 75 cm 2 flasks.
  • CL receptor and RAMPl expression constructs are co-trans fected in equal amounts. Twenty-four hours after transfection the cells are diluted and selective medium (growth medium + 300 ⁇ g/mL hygromycin and 1 ⁇ g/mL puromyc ⁇ n) is added the following day. A clonal cell line is generated by single cell deposition utilizing a FACS Vantage SE (Becton Dickinson). Growth medium is adjusted to 150 ⁇ g/mL hygromycin and 0.5 ⁇ g/mL puromycin for cell propagation.
  • RECOMBINANT RECEPTOR BINDING ASSAY Cells expressing recombinant human CL receptor/RAMPl may be washed with PBS and harvested in harvest buffer containing 50 mM HEPES, 1 mM EDTA and Complete protease inhibitors (Roche). The cell suspension is disrupted with a laboratory homogenizer and centrifuged at 48,000 g to isolate membranes. The pellets are resuspended in harvest buffer plus 250 mM sucrose and stored at - 7O 0 C.
  • binding assays 20 ⁇ g of membranes are incubated in 1 ml binding buffer (10 mM HEPES, pH 7.4, 5 mM MgCl 2 , and 0.2% BSA) for 3 hours at room temperature containing 10 pM 125 LhCGRP (GE Healthcare) and antagonist.
  • the assay is terminated by filtration through 96-well GFB glass fiber filter plates (PerkinElmer) that had been blocked with 0.05% polyethyleneimine.
  • the filters are washed 3 times with ice-cold assay buffer (10 mM HEPES, pH 7.4 and 5 mM MgCl 2 ). Scintillation fluid is added and the plates are counted on a Topcount (Packard).
  • Non-specific binding is determined and the data analysis is carried out with the apparent dissociation constant (K 1 ) determined by using a non-linear least squares fitting the bound CPM data to the equation below:
  • Y max is total bound counts
  • Y mm is non specific bound counts
  • (Y max - Y mm ) is specific bound counts
  • % ⁇ max is the maximum percent inhibition
  • % I min is the minimum percent inhibition
  • radiolabel is the probe
  • Kd is the apparent dissociation constant for the radioligand for the receptor as determined by Hot saturation experiments.
  • Cells may be plated in complete growth medium at 85,000 cells/well in 9 ⁇ well poly ⁇ D- ⁇ ysine coated plates (Coming) and cultured for ⁇ 19 h before assay. According to this procedure, cells are washed with PBS and then incubated with inhibitor for 30 min at 37 0 C and 95% humidity in Cellgro Complete Serum-Free/Low-Protein medium (Mediatech, Inc.) with L-glutamine and 1 g/L BSA. Isobutyl- methy I xanthine is added to the cells at a concentration of 300 ⁇ M and incubated for 30 min at 37 0 C.
  • Human ⁇ -CGRP is added to the cells at a concentration of 0.3 nM and allowed to incubate at 37 0 C for 5 min. After ⁇ -CGRP stimulation the cells are washed with PBS and processed for cAMP determination utilizing the two-stage assay procedure according to the manufacturer's recommended protocol (cAMP SPA direct screening assay system; RPA 559; GE Healthcare).
  • BOP Benzotriazole- 1 -yl-oxy-tris-(dimethylamino)-phosphonium hexafluoropho sphate
  • NaOf-Bw sodium /erf-butoxide
  • HATU 2-(lH-7-Azabenzotriazol-l-yl)-l ,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium
  • BINAP 2,2'-bis(diphenyl phosphino)-l,l'-binaphthyl
  • HMDS hexamethyldi silazane
  • THF tetrahydrof ⁇ ran
  • DMEM Dulbecco's Modified Eagle Medium (High Glucose)
  • FBS fetal bovine serum
  • BSA bovine serum albumin
  • PBS phosphate-buffered saline

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  • Medicinal Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Veterinary Medicine (AREA)
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  • Pain & Pain Management (AREA)
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  • Neurology (AREA)
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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Composés de formule (I), (dans laquelle les variables A1, A2, A3, A4, A5, A6, A7, A8, L, J, Q, R4, Ea, Eb, Ec, R6, R7, Re, Rf, RPG, W, Y et Z sont telles que décrites dans ce document) utiles en tant qu’antagonistes des récepteurs CGRP et utiles dans le traitement ou la prévention de maladies dans lesquelles les récepteurs CGRP sont impliqués, telles que des céphalées, et en particulier la migraine et l’algie vasculaire de la face. L’invention concerne également des compositions pharmaceutiques renfermant ces composés et l’utilisation de ces composés et compositions dans la prévention ou le traitement de ces maladies dans lesquelles les récepteurs CGRP sont impliqués.
EP09818345.2A 2008-10-03 2009-09-29 Antagonistes des récepteurs cgrp Active EP2340025B1 (fr)

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US19514608P 2008-10-03 2008-10-03
PCT/US2009/058711 WO2010039673A1 (fr) 2008-10-03 2009-09-29 Antagonistes des récepteurs cgrp

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EP2340025A1 true EP2340025A1 (fr) 2011-07-06
EP2340025A4 EP2340025A4 (fr) 2012-05-09
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AU2009302712A1 (en) * 2008-10-10 2010-04-15 Merck Sharp & Dohme Corp. CGRP receptor antagonists
EP2846800A4 (fr) * 2012-05-09 2015-11-11 Merck Sharp & Dohme Antagonistes de récepteur de cgrp hétérocycliques
JOP20200116A1 (ar) 2015-04-24 2017-06-16 Amgen Inc طرق لعلاج أو الوقاية من الصداع النصفي
GB201707938D0 (en) 2017-05-17 2017-06-28 Univ Sheffield Compounds
CN111566126A (zh) 2018-01-12 2020-08-21 美国安进公司 Pac1抗体及其用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006029153A2 (fr) * 2004-09-08 2006-03-16 Merck & Co., Inc. Antagonistes de recepteurs cgrp d'anilide spirolactame monocyclique
US20060148779A1 (en) * 2003-03-14 2006-07-06 Bell Ian M Monocyclic anilide spirohydantoin cgrp receptor antagonists
WO2008073251A1 (fr) * 2006-12-08 2008-06-19 Merck & Co., Inc. Composés spirocycliques contraints servant d'antagonistes des récepteurs du cgrp

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
AU2007284994B2 (en) * 2006-05-09 2010-04-22 Merck Sharp & Dohme Corp. Substituted spirocyclic CGRP receptor antagonists

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060148779A1 (en) * 2003-03-14 2006-07-06 Bell Ian M Monocyclic anilide spirohydantoin cgrp receptor antagonists
WO2006029153A2 (fr) * 2004-09-08 2006-03-16 Merck & Co., Inc. Antagonistes de recepteurs cgrp d'anilide spirolactame monocyclique
WO2008073251A1 (fr) * 2006-12-08 2008-06-19 Merck & Co., Inc. Composés spirocycliques contraints servant d'antagonistes des récepteurs du cgrp

Non-Patent Citations (1)

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Title
See also references of WO2010039673A1 *

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WO2010039673A1 (fr) 2010-04-08
EP2340025B1 (fr) 2014-10-15
CA2738657A1 (fr) 2010-04-08
US20110224201A1 (en) 2011-09-15
JP2012504625A (ja) 2012-02-23
US8685965B2 (en) 2014-04-01
EP2340025A4 (fr) 2012-05-09

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